Neurotransmitters

Neurotransmitters

Neurotransmitters are chemicals made by neurons and used by them to transmit signals to the other neurons or non-neuronal cells (e.g., skeletal muscle; myocardium, pineal glandular cells) that they innervate. The neurotransmitters produce their effects by being released into synapses when their neuron of origin fires (i.e., becomes depolarized) and then attaching to receptors in the membrane of the post-synaptic cells. This causes changes in the fluxes of particular ions across that membrane, making cells more likely to become depolarized, if the neurotransmitter happens to be excitatory, or less likely if it is inhibitory.

Neurotransmitters can also produce their effects by modulating the production of other signal-transducing molecules ("second messengers"messengers") in the post-synaptic cells (Cooper, Bloom and Roth 1996). Nine compounds -- belonging to three chemical families -- are generally believed to function as neurotransmitters somewhere in the central nervous system (CNS) or periphery. In addition, certain other body chemicals, for example adenosine, histamine, enkephalins, endorphins, and epinephrine, have neurotransmitter-like properties, and many additional true neurotransmitters may await discovery.

The first of these families, and the group about which most is known, is the amine neurotransmitters, a group of compounds containing a nitrogen molecule which is not part of a ring structure. Among the amine neurotransmitters are acetylcholine, norepinephrine, dopamine, and serotonin.

Acetylcholine is possibly the most widely used neurotransmitter in the body, and all axons that leave the central nervous system (for example, those running to skeletal muscle, or to sympathetic or parasympathetic ganglia) use acetylcholine as their neurotransmitter. Within the brain acetylcholine is the transmitter of, among other neurons, those generating the tracts that run from the septum to the HIPPOCAMPUS, and from the nucleus basalis to the CEREBRAL CORTEX -- both of whbasalis to the CEREBRAL CORTEX -- both of which seem to be needed to sustain memory and learning. It is also the neurotransmitter released by short-axon interneurons of the BASAL GANGLIA.

Norepinephrine is the neurotransmitter released by sympathetic nerves (e.g., those innervating the heart and blood vessels) and, within the brain, those of the locus coeruleus, a nucleus activated in the process of focusing

attention.

Dopamine and Serotonin apparently are neurotransmitters only within the CNS. Some dopaminergic (i.e., dopamine-releasing) neurons run from the substantia nigra to the corpus striatum; their loss gives rise to the clinical manifestations of Parkinson's Disease (Korczyn 1994); others, involved in the rewarding effects of drugs and natural stimuli, run from the mesencephalon to the nucleunucleus accumbens.

The second neurotransmitter family includes amino acids, compounds that contain both an amino group (NH2) and a carboxylic acid group (COOH) and which are also the building blocks of peptides and proteins. The amino acids known to serve as neurotransmitters are glycine, glutamic and aspartic acids, all present in all proteins, and gamma-amino butyric acid (GABA), produced only in brain neurons. Glutamic acid and GABA are the most abundant neurotransmitters within the central nervous system, particularly in the cerebral cortex; glutamic acid tends to be excitatory and GABA inhibitory. Aspartic acid and glycine subserve these functions in the spinal cord (Cooper, Bloom, and Roth 1996).

The third neurotransmitter family is composed of peptides, compounds that contain at least two and sometimes as many as 100 amino acids. Peptide neurotransmitters are poorly understood: Evidence that they are, in fact, transmitters tends to be incomplete, and restricted to their location within nerve terminals, and the physiologic effects produced when they are applied to neurons. Probably the best understood peptide neurotransmitter is substance P, a compound that transmits signals generated by pain.

In general each neuron uses only a single compound as its neurotransmitter. However some neurons contain both an amine and a peptide, and may release both into synapses. Moreover, many neurons release adenosine, an inhibitory compound, along with their "true" transmitter, for instance, norepinephrine or acetylcholine. The stimulant effect of caffeine results from its ability to block receptors for this adenosine.

Neurotransmitters are manufactured from circulating precursor compounds like amino acids, glucose, and the dietary amine choline. Neurons modify the structure of these precursor compounds through a series of enzymatic reactions that often are limited not by the amount of enzyme present but by the concentration of the precursor -- which can change, for example, as a consequence of eating (Wurtman 1988). Neurotransmitters that come from amino acids include serotonin, which is derived from tryptophan; dopamine and norepinephrine, which are derived from tyrosine; and glycine, which is derived from threonine. Among the neurotransmitters made from glucose are glutamate, aspartate, and GABA. Choline serves as a the precursor for acetylcholine.

Once released into the synapse, each neurotransmitter combines chemically with one or more highly specific receptors; these are protein molecules which are imbedded in the post-synaptic membrane. As noted above, this interaction can affect the electrical properties of the post-synaptic cell, its chemical properties, or both. When a NEURON is in its resting state, it sustains a voltage of about -70 millivolts as the consequence of differences between the concentrations of certain ions at the internal and external sides of its bounding membrane. Excitatory neurotransmitters either open protein-lined channels in this membrane, allowing extracellular ions, like sodium, to move into the cell, or close channels for potassium. This raises the neuron's voltage towarpotassium. This raises the neuron's voltage towards zero, and makes it more likely that -- if enough such receptors are occupied -- the cell will become depolarized. If the postsynaptic cell happens also to be a neuron (i.e., as opposed to a muscle cell), this depolarization will cause it to release its own neurotransmitter from its terminals. Inhibitory neurotransmitters like GABA activate receptors that cause other ions -- usually chloride -- to pass through the membrane; this usually hyperpolarizes the postsynaptic cell, and decreases the likelihood that it will become depolarized. (The neurotransmitter glutamic acid, acting via its NMDA receptor, can also open channels for calcium ions. Some investigators believe that excessive activation